PROJECT SUMMARY Frontotemporal dementia (FTD) is often described as an Alzheimer disease (AD) related dementia due to clinical, pathological and genetic overlap. Genetic research has identified several genes contributing to FTD pathogenesis. However, these genes do not explain disease in many familial and sporadic FTD cases and are mostly identified in non-Hispanic white (NHW) populations; indicating a clear gap in our knowledge of underlying genetic factors, especially in diverse population groups. Recent research in AD has identified disease variants and/or variant effects specific to certain population groups (e.g. ABCA7 deletions in African Americans (AA)5 and reduced APOE?4 effect on African background in AA6 and Hispanic (HI) patients (Rajabli et al, under review), warranting research in these diverse populations to assess the full disease variant spectrum. The underrepresentation of HI and AA in biomedical research also represents a major source of health disparity. Additionally, a recent study in the large AD Sequencing Project (ADSP) consortium indicated contribution of FTD known disease genes in a portion of adjudicated AD cases, supporting a true genetic overlap between two disorders. Taken together, these data suggest missing data on potentially shared genetic factors and warrant further analyses of FTD genes in FTD and AD cohorts, especially those encompassing HI patients. To assess the contribution of known FTD disease genes and identify novel FTD disease variants in diverse populations of FTD and AD patients, we will complete the following aims: (1) we will establish a local Miami FTD cohort representative of the population proportions in Miami. This Caribbean enriched cohort will have a wide variety of different levels of ancestral contribution (European, African or American Indian), allowing it to inform on variants in those backgrounds. (2) We will perform GSA genotyping and imputation to obtain data on known FTD variants in the local diverse cohort. Local ancestry across these loci will be determined and variant frequencies in cases will be compared to controls (derived from ADSP/FUS efforts) within population group and within ancestral origin of the variant. (3) We will perform whole genome sequencing in FTD families, prioritizing HI patients and families with early onset disease, and perform sharing analyses to identify novel disease variants. Identified variants of interest will be screened in the remainder of the patients and in collaborative HI FTD cohorts (UCSF, Miller). Additionally, we will extract these novel variant positions from already available data in ADSP/FUS cohorts; including Puerto Rican, Peruvian and African American datasets, to assess genetic overlap with AD. This proposal will leverage all genomic expertise, pipelines and data that are available through the ADSP/FUS consortium efforts, extending on the analyses already performed within the ADSP datasets and expanding the utility of the data generated within ADSP and related projects to AD related dementia research. We will aim to extend this pilot into the current established ADSP collaborations in Puerto Rico and Peru.